DESCRIPTION (provided by investigator): Burkholderia pseudomallei is a bioterrorist threat. With the best current therapies, lethality is typically as high as 40%. The overall goal of this application is the development of new drugs against this organism. In Phase I, we will exploit the high sequence similarity between B. pseudomallei and its less virulent relative Pseudomonas aeruginosa to build innovative screens for rapid, safe discovery of effective therapeutic agents. The two species are similar in genome size and composition, with nucleotide and amino acid sequence identities for many genes in the 50-70% range, and in their mechanisms of drug resistance. We will identify genes for new drug targets in B. pseudomallei with orthologs in P. aeruginosa, validate them as essential for survival or growth of both species, and move them into P. aeruginosa as replacements for the native orthologs. Then, we will measure the whole-genome expression profile of P. aeruginosa strains engineered to under express each B. pseudomallei target gene, and use the results to construct a validated set of sensitive whole-cell reporter screens. In Phase II, we will apply these screens to a library of over 100,000 compounds and advance the most promising candidates into lead optimization and efficacy testing in animal models.